After Republican Senator Ron Gould left the Legislature and left the District 5 seat open, Ward won the three-way August 28, 2012, Republican primary in a highly contested election with 9,925 votes (42.2%,) in a field which included State Representative Nancy McLain.[5] Ward won the November 6, 2012 general election with 49,613 votes (71.2%) against Democratic nominee Beth Weiser,[6] who had run for a Senate seat in 2010.

Ward changed her position on abortion since 2012. In an interview with Arizona's Yellow Sheet Report in 2012, Ward said that she wanted the government to play no role in the decision to have an abortion, saying, "My preference would be that a patient and a doctor talk to each other about the risks, the benefits, what is the potential outcome for the mother should she choose to have a procedure like that, instead of having the government trying to make those decisions.” In 2016, she described herself as "pro-life." Her spokesman Stephen Sebastian said that she maintained a pro-life record in the state senate and supported a "human life amendment" to the U.S. Constitution. She said that Planned Parenthood "sells dismembered baby body parts."[7]

In January 2014, Ward introduced the Arizona Fourth Amendment Protection Act, which would "ban the state from engaging in activities which help the NSA carry out their warrantless data-collection programs, or even make use of the information on a local level."[8][9]

When Ward ran for re-election in November 2014, she was unopposed in both the primary and the general election.

On July 14, 2015, Ward announced she would be entering the race for the Republican nomination for U.S. Senate in Arizona, against long-time incumbent John McCain, who was viewed by many political analysts as a top target of the Tea Party movement and by other Republican conservatives.[10] On December 2, 2015, Ward announced she would be resigning from the Arizona State Senate, effective December 15, in order to dedicate her time to running for the U.S. Senate.[11] She was succeeded by Sue Donahue.[12]

On July 11, 2016, Ward published an ad on her Facebook page saying that John McCain, her primary opponent for the 2016 Republican primary Senate election, was too friendly with Secretary Hillary Clinton. The ad said that they were nearly identical in their political beliefs, stating that "they agree" on issues such as "amnesty for illegal immigrants," opposing President George W. Bush's tax cuts, a gasoline tax, and "blocking conservative judges."[13] The ad was an identical copy of a 2008 ad published by then-presidential candidate Mitt Romney, except that Ward replaced Romney's approval message at the end of the video with her own.[14] Romney's lawyers contacted Ward and her campaign ordering her to cease any further use of the ad, stating Romney for President did not authorize any use of the ad.[15] Ward's campaign did not dispute the similarities, telling reporters that "Mitt Romney got it right." Stephen Sebastian, Ward's spokesman, added "If the shoe fits, wear it. The substance is still the same. Some things never change."[16]

In July 2017, after McCain was diagnosed with brain cancer, Ward said that she hoped that McCain would resign as quickly as possible.[18]

Ward said in a radio interview, "I hope that Senator McCain is going to look long and hard at this, that his family and his advisers are going to look at this, and they're going to advise him to step away as quickly as possible. So that the business of the country and the business of Arizona being represented at the federal level can move forward. ... We can't have until the 2018 election, waiting around to accomplish the Trump agenda, to secure the border and stop illegal immigration and repeal Obamacare and fix the economy and fix the veterans administration, all those things need to be done and we can't be at a standstill while we wait for John McCain to determine what he's going to do."[18]

Ward said that she hoped that Arizona's governor would consider appointing her to fill McCain's seat.[19]

In October 2016, Ward announced that she would run in the 2018 Republican primary against incumbent Senator Jeff Flake (who later announced he would leave the Senate).[2][3] Ward has criticized Flake for being “an open-borders, amnesty globalist,” describing herself as “a build-the-wall, stop-illegal-immigration Americanist.”[20]

Also in that month, a video attack ad appeared accusing Ward of agreeing with the chemtrails conspiracy theory and referring to her as “Chemtrail Kelli”. The advertisement was sponsored by the Senate Leadership Fund, aligned with Senate Majority LeaderMitch McConnell,[23][20] and may have been the first time Ward came to the attention of "many outside Arizona" according to journalist Clare Malone,[20] (an ad on the subject of chemtrails and Ward first appeared in the 2016 Senate race with McCain).[24]Politifact rated the claim that Ward "hosted a town hall on 'chemtrail conspiracy theories' and is open to sponsoring chemtrails legislation" as "mostly false",[23] and factcheck.org labeled the ad "misleading".[25] Ward criticized the ad as demonstrating "sexism reserved for conservative women".[20]

Ward has been endorsed by Sean Hannity,[26] Mark Levin,[27] Laura Ingraham,[28] Rep. Steve King,[29] and Sen. Rand Paul.[30][31] Ward was endorsed by President Trump saying: "Great to see that Dr. Kelli Ward is running against Flake Jeff Flake, who is WEAK on borders, crime and a non-factor in Senate. He's toxic!"[32][33][34]

In October 2017, Ward was formally endorsed by conservative Breitbart figure Steve Bannon in her 2018 race against Senator Jeff Flake. Ward appeared together with Bannon to announce the endorsement.[35] She was also endorsed by Great America PAC, which has been described as "an arm of Team Bannon." Bannon has said he believes Ward will help build a wall on the southern border of the US and repeal the Affordable Healthcare Act.[36] Ward has since attempted to distance herself from Bannon in the aftermath of Bannon's public falling-out with Trump, whose endorsement Ward is also seeking, according to The Arizona Republic.[35]